Belzutifan, A Hypoxia-Inducible Factor 2-Alpha Inhibitor, for Patients with Advanced Pheochromocytoma and Paraganglioma

Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms arising from the sympathetic and parasympathetic nervous systems. Their heterogeneous clinical behavior and metastatic potential present significant management challenges. Pseudohypoxia driven by oxygen metabolism dysregulation is the central oncogenic mechanism in Cluster 1 PPGLs, which carry the highest metastatic risk. In these tumors, pathogenic variants in the succinate dehydrogenase complex (SDHx) or von Hippel–Lindau (VHL) gene create an intracellular environment that mimics chronic hypoxia, leading to hypoxia inducible factor 2 alpha (HIF 2α) activation and driving the hypervascularity and aggressive clinical phenotype.

Belzutifan, a first in class selective HIF 2α inhibitor, has emerged as a promising therapeutic strategy for pseudohypoxia driven PPGLs. In the LITESPARK 015 phase 2 trial, belzutifan achieved a disease control rate of 85% and an overall response rate of 26% in patients with locally advanced or metastatic disease. Beyond radiographic outcomes, belzutifan provides meaningful clinical benefits, including improved blood pressure control and enhanced quality of life. Unlike cytotoxic therapies, belzutifan’s safety profile is characterized by predictable, mechanism-based adverse events, most commonly grade 1–3 anemia. Belzutifan is the first oral and the second FDA-approved therapy for metastatic PPGLs establishing a new therapeutic option for these complex rare tumors. While its development underscores the utility of precision oncology, definitive molecular correlations with clinical efficacy remain to be demonstrated.